Neonates with hypoxic-ischemic encephalopathy treated with hypothermia: Observations in a large Canadian population and determinants of death and/or brain injury

Abstract

BACKGROUND:

Birth asphyxia in term neonates remains a serious condition that causes significant mortality and long-term neurodevelopmental sequelae despite hypothermia treatment. The objective of this study was to review therapeutic hypothermia practices in a large population of neonates with hypoxic-ischemic encephalopathy (HIE) across Canada and to identify determinants of adverse outcome.

METHODS:

Our retrospective observational cohort study examined neonates≥36 weeks, admitted to the Canadian Neonatal Network NICUs between 2010 and 2014, diagnosed with HIE, and treated with hypothermia. Adverse outcome was defined as death and/or brain injury. Maternal, birth, and postnatal characteristics were compared between neonates with adverse outcome and those without. The association between the variables which were significantly different (p < 0.05) between the two groups and adverse outcome were further tested, while adjusting for gestational age, birth weight, gender, and initial severity of encephalopathy.

RESULTS:

A total of 2187 neonates were admitted for HIE; 52% were treated with hypothermia and 40% developed adverse outcome. Initial severity of encephalopathy (moderate, p = 0.006; severe, p < 0.0001), hypotension treated with inotropes (p = 0.001), and renal failure (p = 0.007) were significantly associated with an increased risk of death and/or brain injury.

CONCLUSIONS:

In asphyxiated neonates treated with hypothermia, not only their initial severity of encephalopathy on admission, but also their cardiac and renal complications during the first days after birth were significantly associated with risk of death and/or brain injury. Careful monitoring and cautious management of these complications is warranted.

Keywords

Birth asphyxia hypoxic-ischemic encephalopathy brain injury magnetic resonance imaging

Abbreviations

CNN

Canadian Neonatal Network

MRI

Magnetic resonance imaging

HIE

Hypoxic-ischemic encephalopathy

NICUs

Neonatal intensive care units

1 Introduction

Despite improvements in neonatal care, birth asphyxia in term neonates remains a serious condition that causes significant mortality and neurodevelopmental sequelae [1, 2]. Currently, the only proven effective treatment for birth asphyxia is therapeutic hypothermia [3 –9]. Since 2010, hypothermia has been increasingly used in the tertiary-level neonatal intensive care units (NICUs) across Canada for neonates with birth asphyxia. Despite the overall improvement in reducing neonatal mortality and morbidity, some treated neonates still die and/or develop brain injury [10, 11]. It remains important to identify the perinatal determinants of death and/or brain injury in these asphyxiated neonates treated with hypothermia. Other studies have looked at these possible risk factors in small samples of asphyxiated neonates [12]. Validation of these potential risk factors in a large population of asphyxiated neonates treated with hypothermia is required.

Our objectives were to review therapeutic hypothermia practices in a large population of asphyxiated neonates treated with hypothermia across Canada and identify maternal, birth and postnatal risk factors associated with adverse outcome in those neonates.

2 Subjects and methods

2.1 Study design

We conducted a retrospective observational cohort study using data from the Canadian Neonatal Network (CNN) database. The CNN maintains a national perinatal-neonatal database that collects data on all neonates born at≥36 weeks’ gestational age admitted to 28 tertiary-level NICUs in Canada. Data were abstracted from medical records at each site according to standardized definitions and electronically transmitted to the CNN coordinating center as previously described [13]. As shown previously, the CNN database is remarkably consistent and reliable [14]. Data collection at each site was approved by the respective institutional research ethics board or appropriate quality improvement committee. The retrospective evaluation of de-identified data for this study was approved by the local institutional research ethics board and the CNN Executive Committee.

2.2 Study population

Neonates with a≥36 weeks’ gestational age, a birth weight of≥1800 grams, and admitted to one of the CNN tertiary-level NICUs between January 2010 and December 2014 with a diagnosis of HIE were included in this study, as per the criteria used for cooling in Canada. Diagnosis of HIE was based on the presence of encephalopathy on admission, in association with (1) a documented acute perinatal event (e.g., fetal distress, cord prolapse, uterine rupture, reduced fetal movements, abruption, antepartum hemorrhage, or emergent caesarean section due to fetal distress), and (2) an evidence of intrapartum hypoxia (at least one of the following: 10-minute Apgar score≤5, mechanical ventilation or resuscitation within 10 minutes, and/or cord pH < 7.00 or postnatal arterial pH < 7.00 or base deficit≤– 12 within 60 minutes of birth). Initial severity of encephalopathy on admission was classified as mild, moderate, or severe using standard definitions reported by Sarnat [15]. Timing to initiation of hypothermia treatment was also recorded. Neonates with major congenital anomalies were excluded.

2.3 Variables and outcome

Study variables were defined according to the CNN Abstractors’ Manual [13]. Maternal, birth, and postnatal characteristics of the neonates included in our cohort were analyzed. Maternal variable included maternal age, parity, maternal diabetes, and maternal hypertension. Birth variables included the general characteristics of the neonates, such as birth weight, gestational age, small for gestational age (<10^th percentile), and gender, as well as the mode of delivery, the duration of rupture of membranes, the presence of chorioamnionitis, and the resuscitation details. Postnatal variables included resuscitation details, as well as presence of seizures, hypotension, persistent pulmonary hypertension, renal failure, early onset sepsis, and meningitis. Hypotension treated with inotropes was recorded; the use of epinephrine for initial resuscitation was not considered in this diagnosis. Persistent pulmonary hypertension was defined by clinical and echocardiographic evidence of pulmonary hypertension, and the use of inhaled nitric oxide. Renal failure was defined as urine output < 0.5 ml/kg/hour and/or rising creatinine > 100 mmol/L at any time within the first 72 hours of life.

Adverse outcome was defined as death and/or evidence of brain injury on brain magnetic resonance imaging (MRI) scans. Presence of brain injury was noted if injury to basal ganglia, white matter, and/or grey matter were identified on their brain magnetic resonance imaging. Abstractors recorded the neuroimaging report performed during hospitalization and when there was more than one report, the highest severity of MRI finding was used. Image interpretation was based on the final radiological report in each center.

2.4 Statistical analysis

Descriptive statistical methods were used to summarize the study cohort. Birth and postnatal characteristics were compared between asphyxiated neonates treated with hypothermia who developed adverse outcome and those who did not, using the chi-square test or Fisher’s exact test for categorical variables and student t-test or Mann-Whitney test for continuous variables. A multivariate logistic regression was used to assess the association between the perinatal variables which were significantly different (p < 0.05) between the two groups and adverse outcome (i.e., death and/or brain injury), while adjusting for gestational age, birth weight, gender, and initial severity of encephalopathy on admission (corresponding to the initial neurological examination on admission to one of the CNN tertiary-level NICUs). Statistical analyses were performed using SAS 9.3 (SAS Institute, Cary, North Carolina, USA). A two-sided significance level of 0.05 was used without adjustment for multiple comparisons.

3 Results

Between 2010 and 2014, 71015 neonates were admitted to the CNN tertiary-level NICUs (Fig. 1). Of these, 32 700 had a gestational age≥36 weeks and a birth weight≥1800 grams. A total of 2187 (6.7%) neonates were admitted with a diagnosis of HIE. Among the neonates diagnosed with HIE, 38% (814/2187) were not treated with hypothermia, and 52% (1144/2187) were treated with hypothermia (Fig. 1). Among the neonates not treated with hypothermia, 56% (453/814) were mildly encephalopathic, 18% (144/814) were moderate, 7% (60/814) were severe, and information on severity of encephalopathy was not available in 19% (157/814). Reasons for not cooling neonates with moderate or severe HIE included delayed transfer, lack of policy/equipment for cooling, extreme condition, clinical team decision, and head trauma or intracranial hemorrhage.

Fig. 1

Flow chart of the neonates included in the study. Abbreviations: BW, birth weight; GA, gestational age; w, weeks’; g, grams; n, number in group; HIE, hypoxic-ischemic encephalopathy; MRI, magnetic resonance imaging.

Among neonates treated with hypothermia, initial severity of encephalopathy was mild in 19% (221/1144), moderate in 49% (565/1144), severe in 25% (290/1144), and information on severity of encephalopathy was not available in 6% (68/1144). Among those neonates, 86% (983/1144) survived and 14% (161/1144) died. Brain MRI results were available in 89% (877/983) of surviving neonates and in 52% (83/161) of those who died. Among the surviving neonates without brain MRI (n = 102), 30% (31/102) were mildly encephalopathic, 44% (45/102) were moderate, and 13% (13/102) were severe. Four surviving neonates had no available information about brain MRI. For those who died with available brain imaging (n = 83), mean age at the time of death was 10.8±10.9 days (range: 1– 57). Reported causes of deaths included (severe) encephalopathy, brain injury, multiorgan failure, cardiorespiratory failure, persistent pulmonary hypertension, hemorrhagic shock, and/or coagulopathy. For those who died without brain MRI results (n = 78), mean age at the time of death was 3.2±1.8 days (range: 1– 9). Reported causes of deaths included (severe) encephalopathy, multiorgan failure, cardiac dysfunction and refractory hypotension, persistent pulmonary hypertension, renal failure, hepatic failure, hemorrhagic shock, coagulopathy, and/or sepsis. Among the surviving neonates with available brain MRI results (n = 877), 34% (299/877) demonstrated brain injury and 66% (578/877) did not. Thus, for the remaining analysis, 460 neonates were considered as having an adverse outcome (death and/or brain injury) and 578 were not (alive without brain injury on imaging) (Fig. 1).

The birth characteristics, including birth weight, gestational age, proportion of small for gestational age, and gender were similar between both groups of neonates (Table 1). In contrast, asphyxiated neonates with adverse outcome were more often delivered by caesarean section (p < 0.01) and born following a rupture of membranes > 24 hours (p = 0.04). Asphyxiated neonates with adverse outcome had lower Apgar scores at 10 minutes (p < 0.0001). They had a higher incidence of positive pressure ventilation via endotracheal tube (p < 0.0001), and more frequently had chest compressions for more than 30 seconds (p < 0.0001). Asphyxiated neonates with adverse outcome, presented with more severe encephalopathy on admission to the NICU (p < 0.0001), had more often seizures (p < 0.0001), hypotension treated with inotropes (p < 0.0001), persistent pulmonary hypertension (p = 0.0003) and renal failure (p < 0.0001) during their hospitalization than those who survived without brain injury.

Table 1

Clinical characteristics of neonates with HIE and treated with hypothermia

Clinical variables	Alive and no brain injury on MRI	Dead and/or brain injury	p value*	Alive without imaging	p value**
	(n = 460)	(n = 578)		(n = 102)
Maternal characteristics
Maternal age, mean (SD)	30.0 (5.6)	29.9 (5.5)	0.81	30.2 (5.9)	0.73
Parity			0.51	0.66
0, n (%)	339 (59)	281 (61)		56 (55)
1, n (%)	136 (23)	110 (24)		23 (23)
2, n (%)	58 (10)	34 (7)		12 (12)
>3, n (%)	33 (6)	25 (5)		7 (7)
Info not available, n (%)	12 (2)	10 (2)		4 (4)
Maternal diabetes, n (%)	65 (11)	55 (12)	0.65	14 (14)	0.42
Maternal hypertension, n (%)	61 (11)	41 (9)	0.45	11 (11)	0.91
Birth characteristics
Birth weight, mean (SD)	3408 (618)	3369 (581)	0.30	3375 (619)	0.62
Gestational age, mean (SD)	39.1 (1.5)	39.1 (1.5)	0.86	38.9 (1.7)	0.19
Small for gestational age (<10th percentile), n (%)	87 (15)	74 (16)	0.34	15 (15)	0.93
Male, n (%)	336 (58)	255 (55)	0.38	58 (57)	0.81
Cesarean section, n (%)	260 (45)	248 (54)	< 0.01	51 (51)	0.33
Rupture of membranes			0.04		1.00
<24 hours, n (%)	521 (90)	391 (85)		94 (96)
24 hour – 1 week, n (%)	26 (5)	36 (8)		4 (4)
>1 week, n (%)	2 (1)	1 (1)		0
Chorioamnionitis, n (%)	44 (8)	32 (7)	0.89	6 (17)	0.79
Apgar score at 10 minutes
Available in # patients	517	411		90
Median (IQR)	5 (4, 6)	4 (2, 6)	< 0.0001	5 (3, 7)	0.46
Positive pressure ventilation	376 (65)	367 (80)	< 0.0001	60 (59)	0.22
via endotracheal tube, n (%)
Chest compression > 30	175 (30)	245 (53)	< 0.0001	33 (33)	0.68
seconds, n (%)
Postnatal characteristics
Initial severity of encephalopathy			< 0.0001		0.0052
Mild, n (%)	152 (26)	37 (8)		30 (29)
Moderate, n (%)	345 (60)	175 (38)		46 (45)
Severe, n (%)	51 (9)	224 (49)		13 (13)
Not available, n (%)	30 (5)	24 (5)		13 (13)
Time to initiation of hypothermia	4.2 (5)	4.7 (6)	0.15	4.3 (4)	0.73
treatment (hours), mean (SD)
Seizures, n (%)	230 (40)	331 (72)	<0.0001	36 (35)	0.38
Hypotension treated with	181 (31)	256 (56)	<0.0001	32 (31)	0.99
inotropes, n (%)
Persistent pulmonary	89 (15)	112 (24)	0.0003	19 (19)	0.41
hypertension, n (%)
Renal failure, n (%)	124 (21)	197 (43)	<0.0001	24 (24)	0.64
Early onset sepsis, n (%)	1 (1)	3 (1)	0.33	0	1.00
Meningitis, n (%)	0 (0.0)	1 (0.2)	1.00	0	–

Adverse outcome was defined as death without MRI being performed or evidence of injury on a brain MRI. * Comparison between “alive and no brain injury” and “dead and/or brain injury”. * Comparison between “alive and no brain injury” and “alive and no brain imaging”. Abbreviations: n, number in group; IQR, interquartile range; SD, standard-deviation.

In the multivariate analysis that adjusted for gestational age, small for gestational age, gender, initial severity of encephalopathy, hypotension treated with inotropes, persistent pulmonary hypertension, and renal failure, we identified that initial severity of encephalopathy (moderate, p = 0.006; severe, p < 0.0001), hypotension treated with inotropes (p = 0.001), and renal failure (p = 0.007) were significantly associated with an increased odds of death and/or brain injury (Table 2).

Table 2

Multivariate logistic regression to identify determinants of adverse outcome (i.e., death and/or brain injury)

Parameters	OR (95% CI)	p value
Birth weight	1.00 (0.99 – 1.00)	0.18
Small for gestational age	1.18 (0.73 – 1.89)	0.51
Male	1.03 (0.76 – 1.39)	0.85
Initial severity of encephalopathy
Moderate	1.79 (1.18 – 2.70)	0.006
Severe	13.20 (8.08 – 21.56)	< 0.0001
Hypotension treated with inotropes	1.70 (1.23 – 2.35)	0.001
Persistent pulmonary hypertension	1.01 (0.68 – 1.51)	0.95
Renal failure	1.58 (1.14 – 2.20)	0.007

4 Discussion

Birth asphyxia remains a significant problem in Canada with an incidence of 6.7% among NICU admissions with a gestation age≥36 weeks and a birth weight≥1800 grams. Despite improvements in neonatal care and the introduction of therapeutic hypothermia, our study confirmed that many asphyxiated neonates still die and/or develop brain injury. Our mortality rate of 14% was lower than published trials [3 –9], probably related to the facts that some neonates with mild HIE were cooled. We identified initial severity of encephalopathy, hypotension treated with inotropes, and renal failure, as variables independently associated with death or brain injury.

Asphyxiated neonates, who died and/or developed brain injury despite hypothermia, had worse primary adaptation, with a worse Apgar scores, more frequent active resuscitation, and more severe encephalopathy initially. The poor primary adaptation of these neonates suggests that their initial asphyxial event was worse and/or they required more resuscitation within the first minutes of life than neonates who survived without brain injury.

Hypotension treated with inotropes and renal failure were two independent risk factors associated with death and/or brain injury. Other studies have also identified these two neonatal complications as risk factors that contribute to worse outcome [16 –19]. The initial asphyxial event is likely to have compromised the cerebral blood flow autoregulation, and hypotension during the immediate postnatal period may further impair the ability of the asphyxiated neonates to autoregulate cerebral blood flow leading to more severe brain injury [16 , 20– 22]. Hypotension is known to further decrease cerebral blood flow and cerebral oxygen delivery, and decrease oxygen consumption [20 , 23]. Variability in defining hypotension in asphyxiated neonates treated with hypothermia and uncertainty about the best way to manage hypotension in these neonates [16] may also have an impact on the development of adverse outcomes. Insufficient treatment may lead to further decrease in cerebral blood flow [20 , 23]; alternatively, too aggressive management may also have side effects and worsen reperfusion injury, as described in premature neonates [24]. Renal failure has also been linked to worse outcomes [25], especially in the context of perinatal asphyxia. Neonates with acute kidney injury in the context of asphyxia had higher overall mortality, stayed longer in the NICU, and required longer mechanical ventilation than neonates without acute kidney injury [19]. Neonates with acute kidney injury were also more likely to have a brain injury after hypothermia treatment [18]. Further prospective study of the optimal management to treat hypotension and to prevent renal failure in asphyxiated neonates treated with hypothermia is warranted. In the meantime, management of blood pressure and renal function in asphyxiated neonates should probably include a careful individualized approach based on the end-organ damage of each neonate in order to maintain homeostasis as much as possible and prevent ongoing brain injury.

Despite the known benefits of hypothermia, a significant proportion of asphyxiated neonates were not cooled in our study. Most of them had an initial mild encephalopathy. However, 25% of them had a moderate, or severe HIE. The most frequent reason given for not treating these neonates with hypothermia was delayed transfer to a tertiary NICU, which reflects the fact that some asphyxiated neonates are still not recognized within the 6-hour window to benefit from hypothermia and/or they arrive at the tertiary-level NICUs after this timeframe. It probably also reflects that many units across Canada still did not offer passive cooling on transport [26 –28]. Other reasons given for not treating neonates with moderate or severe encephalopathy with hypothermia included the unit policy about cooling and clinical team preference. Even if hypothermia treatment is shown to be less effective in neonates with severe encephalopathy compared to those with moderate encephalopathy [3 –9], it should still be offered as it is still of benefit to some neonates with severe HIE.

Current guidelines recommend hypothermia treatment only for neonates with moderate and severe encephalopathy; however, a substantial proportion (18%, 189/1038) of asphyxiated neonates with mild encephalopathy were treated with hypothermia in this study. HIE stages are a continuum, it is not always easy to differentiate between the different stages when performing a clinical assessment, and some clinical teams may favor cooling when in doubt. In addition, some tertiary-level NICUs use amplitude-integrated electroencephalogram, in addition to the clinical assessment, to evaluate the initial severity of encephalopathy during the study period [30], and mild encephalopathy on clinical assessment may correspond to moderate encephalopathy on amplitude-integrated electroencephalogram. Other studies have also demonstrated that some centers cool neonates with mild HIE, because these neonates may still be at risk of adverse outcome [30 –35]. In our study, 20% (37/189) of these neonates treated with hypothermia died or developed brain injury. The current study did not permit us to evaluate the effect of hypothermia treatment on brain injury in neonates with mild HIE, because brain MRIs were not systematically performed in the neonates with mild HIE who were not cooled.

The main strength of our study is that it is a large cohort of 1144 neonates treated with hypothermia, allowing for an observation of practices in Canada and for assessing the determinants of death and/or brain injury. The main limitation of this study is that a brain MRI is not performed systematically on all asphyxiated neonates treated with hypothermia across Canada [36]. This fact is illustrated by the 11% of asphyxiated neonates treated with hypothermia who survived but did not have brain imaging. Reasons for not performing brain MRIs, especially in the surviving neonates, were not available in the CNN database. In addition, a detailed neurological examination at discharge such as Prechtls’ General Movements Assessment (GMA) or a Hammersmith Infant Neurological Examination (HINE) was not systematically performed in these asphyxiated neonates [37] and their long-term neurodevelopment outcomes were not available through the database, so we used brain injury on imaging as a surrogate of future outcome. Neuroimaging in the perinatal period is able to provide information about the extent of brain injury [38, 39], and is predictive of later outcomes [40 –42]. However, using neuroimaging instead of the long-term neurodevelopmental outcomes may have overestimated the number of neonates with adverse outcomes, because not all neonates with brain injury develop major disability [40 –42]. In our study, presence of brain injury was noted if injury to basal ganglia, white matter, and/or grey matter were identified on their brain magnetic resonance imaging; however, another limitation of our study was that it was not possible to differentiate further the neonates into basal ganglia injury pattern, watershed pattern or total injury pattern since the detail of the brain injury was not collected separately in the database. Finally, arterial cord pH was not available in all newborns, as not systematically performed in all newborns, and thus could not be included in our multivariate logistic regression to predict outcome [43, 44]. Initial neurological examination on admission to one of the CNN tertiary-level NICUs was discussed in term of modified Sarnat score and was used to define the initial severity of encephalopathy, which was taken into account in the multivariate logistic regression.

In conclusion, HIE remains a significant problem in Canada and many neonates asphyxiated still die and/or develop brain injury. We demonstrated in a large population of neonates that not only their initial severity of encephalopathy, but also their cardiac and renal complications during the first days of life were significantly associated with their risk of death and/or brain injury. It would be important to study in the future whether a strict monitoring of blood pressure and its careful correction, as well as an individualized fluid management to reduce the impact of renal dysfunction should be targeted for asphyxiated neonates to maintain homeostasis as much as possible and prevent ongoing brain injury. General national guidelines should be developed for assessing initial severity of encephalopathy, imaging brain injury, and following up on the neurodevelopmental outcomes of asphyxiated neonates treated with hypothermia to better understand how initial treatments and risk factors impact outcome.

6 Disclosure statements

The authors declare no conflict of interest. Although no specific funding was received for this study, organizational support for the Canadian Neonatal Network was provided by the Maternal-Infant Care Research Centre (MiCare) at Mount Sinai Hospital in Toronto, Ontario, Canada. MiCare is supported by a Canadian Institutes of Health Research (CIHR) Team Grant (FRN87518) and in-kind support from Mount Sinai Hospital. Dr. Shah holds an Applied Research Chair in Reproductive and Child Health Services and Policy Research awarded by the CIHR (APR-126340). The funding agencies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Footnotes

Acknowledgments

The authors gratefully acknowledge all site investigators and data abstractors of the CNN. We extend our thanks to the staff at the Maternal-Infant Care Research Centre at Mount Sinai Hospital, Toronto, ON, for providing organizational support for this project. We also thank Sarah Hutchinson, PhD, from the Maternal-Infant Care Research Centre for editorial assistance in the preparation of this manuscript.

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